Energy Distribution in disordered elastic Networks

Disordered networks are found in many natural and artificial materials, from gels or cytoskeletal structures to metallic foams or bones. Here, the energy distribution in this type of networks is modeled, taking into account the orientation of the struts. A correlation between the orientation and the energy per unit volume is found and described as a function of the connectivity in the network and the relative bending stiffness of the struts. If one or both parameters have relatively large values, the struts aligned in the loading direction present the highest values of energy. On the contrary, if these have relatively small values, the highest values of energy can be reached in the struts oriented transversally. This result allows explaining in a simple way remodeling processes in biological materials, for example, the remodeling of trabecular bone and the reorganization in the cytoskeleton. Additionally, the correlation between the orientation, the affinity, and the bending-stretching ratio in the network is discussed

Just a 'romantic idea'? A theory-based interview study on medication review implementation with pharmacy owners.

Recent legal changes in Germany entitle patients on multiple medications to receive a medication review (MR). However, the provision of MRs is not mandatory and pharmacy owners decide whether to implement this service in their pharmacies. The aim of this study was to determine pharmacy owners' attitudes towards MRs, explore their experiences with MR implementation and examine their perceptions of barriers and facilitators towards implementation of MRs in community pharmacies. Pharmacy owners were invited to participate in semi-structured interviews. Purposive sampling was used with selection criteria being MR-implementation stage, and geographical location of the pharmacy. The topic guide was based on a systematic review and the Framework for Implementation of Services in Pharmacy (FISpH). Interviews were recorded, transcribed verbatim and coded directly against the FISpH. Twenty-one pharmacy owners were interviewed. Despite participants' consistent positive attitude towards MRs, most believed that providing MRs on an economically viable basis would be challenging. Several practical suggestions emerged which would enable community pharmacies a smoother implementation of MRs. Suggestions included employing ‘change facilitators', who visit and support implementing pharmacies; national awareness campaigns targeting patients and health professionals; reducing bureaucracy; continuing professional development; involving technicians in some MR-tasks; and offering an additional incentive to lower the initial implementation threshold. This research identified numerous factors that are likely to increase owners' and managers' support to the idea of MRs. This may be of interest to any country planning implementation of MRs

Bioresonance According to Paul Schmidt (BaPS) and its Beneficial Effects on the Integrity of the Intestinal Barrier in vitro

The intestinal epithelium, which is only one cell layer thick, has two essential tasks. The first is to create a physical barrier between the contents of the intestinal lumen and the rest of our body. The second is to ensure an efficient absorption of essential nutrients from the gut lumen and to produce mucus, anti-microbial peptides and cytokines with both protective and immune-regulatory properties. Thus, a reduced barrier function may have consequences, not only for intestinal, but also for systemic health. In this study we investigated whether the use of a Mini-Rayonex device, which has been developed to emit a bioresonance frequency spectrum according to Paul Schmidt (BaPS), might be able to promote and maintain the integrity of the intestinal barrier

Facilitating implementation of medication reviews in the community pharmacy setting: an application of the implementation research logic model.

Previous research has identified both determinants and potential strategies to facilitate implementation of medication reviews (MR). A conceptual model which links determinants, strategies to support implementation and mechanisms of change to execute implementation, with projected outcomes is helpful to plan the approach and facilitate MR-implementation. The aim of this research was to apply the Implementation Research Logic Model (ILRM) for the implementation of medication reviews in the German community pharmacy setting, and thus illustrate the links between determinants, strategies, and implementation outcomes. The resulting map is meant to inform and facilitate MR-implementation. The IRLM was populated with determinants (barriers and facilitators structured using the Framework for Implementation of Services in Pharmacy, FISpH), proposed strategies (according to the Expert Recommendations for Implementing Change, ERIC) and mechanisms of change which were identified in an interview study with 21 German pharmacy owners. The research team linked these with 8 implementation outcomes derived from Proctor: acceptability, adoption, appropriateness, cost, feasibility, fidelity, penetration, sustainability. Twenty strategies from the interview study were mapped against 32 determinants. All strategies were hypothesised to impact on one or several of the 8 implementation outcomes. Depending on pharmacies' implementation stage (exploration, preparation, implementation, and sustainment) the importance of strategies was expected to vary. Strategies such as educational meetings and learning collaboratives can increase perceived appropriateness and boost adoption of MRs which is particularly important for pharmacies in the early exploration stage. Strategies such as receiving support from external implementation advisors as well as recruiting and training internal implementation leaders were deemed particularly important for pharmacies at the preparation stage to strengthen feasibility and fidelity. In later stages (implementation and sustainment) pharmacies were thought to benefit from provision of clinical feedback, obtaining and using patient feedback and re-examining implementation to achieve high fidelity, penetration, and sustainability of MR-provision. Some strategies such as fixed payment and stable delivery contracts were deemed pre-requisites for implementation irrespective of the stage the pharmacy was at. The application of the Implementation Research Logic Model illustrated the relations between determinants, strategies, mechanisms, and implementation outcomes. Future research is needed to ascertain that strategies work as planned and achieve the projected implementation outcomes

Implementation of medication reviews in community pharmacy: reaching consensus on stakeholders' recommendations for mechanisms of change using the nominal group technique.

Since 2022, patients with five or more medicines are eligible for a medication review (MR) in a community pharmacy remunerated by the German health system. However, implementation has been slow, with few pharmacies providing MRs. Stakeholders' input is necessary to detail how implementation strategies can be executed effectively on a national level. Prior research identified "external facilitation" and "altering incentives" as crucial strategies to achieve implementation outcomes. To gather stakeholders’ recommendations for, and obtain consensus on, mechanisms of change that allow implementation strategies to work in practice. The consensus method used was the nominal group technique (NGT) with NGT-discussions held separately with pharmacy owners and pharmacy chambers employees. Votes were summed and the relative importance (rI) calculated, defined as (score achieved for a mechanism)/(maximum possible score) × 100. Content analysis provided context for the highest ranked mechanisms and allowed linking to implementation outcomes. Four NGT-discussions were held in 2023 (n = 2 owners; n = 2 chamber employees) with a total of 17 participants. The overall highest ranked mechanisms were fit-for-purpose software (rI = 154.7) detailed process support (rI = 104.9) and an expert support line (rI = 77.7). These together with financial viability (rI = 40.0) were prioritised by both participant groups. Three mechanisms were favoured for both implementation strategies, namely software, process support and materials (rI = 34.3). This study identified stakeholders' priorities for mechanisms of change to implement MRs in community pharmacies. Focusing efforts on the prioritised mechanisms is likely to significantly advance a national implementation plan for countries which are at an early implementation stage

Pathogenic variants associated with dilated cardiomyopathy predict outcome in pediatric myocarditis

BACKGROUND: Myocarditis is one of the most common causes leading to heart failure in children and a possible genetic background has been postulated. We sought to characterize the clinical and genetic characteristics in patients with myocarditis ≤18 years of age to predict outcome. METHODS: A cohort of 42 patients (MYCPEDIG) with biopsy-proven myocarditis underwent genetic testing with targeted panel sequencing of cardiomyopathy-associated genes. MYCPEDIG patients were divided into subgroups according to the phenotype of dilated cardiomyopathy (DCM) at presentation, resulting in 22 patients without DCM (MYC-NonDCM) and 20 patients with DCM (MYC-DCM). RESULTS: MYC-DCM patients (median age 1.4 years) were younger than MYC-NonDCM patients (median age 16.1 years; p<0.001) and were corresponding to heart failure-like and coronary syndrome-like phenotypes, respectively. At least one likely pathogenic/pathogenic (LP/P) variant was identified in 9/42 patients (22%), 8 of them were heterozygous, and 7/9 were in MYC-DCM. LP/P variants were found in genes validated for primary DCM (BAG3, DSP, LMNA, MYH7, TNNI3, TNNT2, and TTN). Rare variant enrichment analysis revealed significant accumulation of high impact disease variants in MYC-DCM versus healthy individuals (p=0.0003). Event-free survival was lower (p=0.008) in MYC-DCM patients compared to MYC-NonDCM and primary DCM. CONCLUSIONS: We report heterozygous LP/P variants in biopsy-proven pediatric myocarditis. Myocarditis patients with DCM phenotype were characterized by early-onset heart failure, significant enrichment of LP/P variants, and poor outcome. These phenotype- and age-group specific findings will be useful for personalized management of these patients. Genetic evaluation in children newly diagnosed with myocarditis and DCM phenotype is warranted

Quantification of the Temporal Evolution of Collagen Orientation in Mechanically Conditioned Engineered Cardiovascular Tissues

Load-bearing soft tissues predominantly consist of collagen and exhibit anisotropic, non-linear visco-elastic behavior, coupled to the organization of the collagen fibers. Mimicking native mechanical behavior forms a major goal in cardiovascular tissue engineering. Engineered tissues often lack properly organized collagen and consequently do not meet in vivo mechanical demands. To improve collagen architecture and mechanical properties, mechanical stimulation of the tissue during in vitro tissue growth is crucial. This study describes the evolution of collagen fiber orientation with culture time in engineered tissue constructs in response to mechanical loading. To achieve this, a novel technique for the quantification of collagen fiber orientation is used, based on 3D vital imaging using multiphoton microscopy combined with image analysis. The engineered tissue constructs consisted of cell-seeded biodegradable rectangular scaffolds, which were either constrained or intermittently strained in longitudinal direction. Collagen fiber orientation analyses revealed that mechanical loading induced collagen alignment. The alignment shifted from oblique at the surface of the construct towards parallel to the straining direction in deeper tissue layers. Most importantly, intermittent straining improved and accelerated the alignment of the collagen fibers, as compared to constraining the constructs. Both the method and the results are relevant to create and monitor load-bearing tissues with an organized anisotropic collagen network

Colocalization of connexin 36 and corticotropin-releasing hormone in the mouse brain

<p>Abstract</p> <p>Background</p> <p>Gap junction proteins, connexins, are expressed in most endocrine and exocrine glands in the body and are at least in some glands crucial for the hormonal secretion. To what extent connexins are expressed in neurons releasing hormones or neuropeptides from or within the central nervous system is, however, unknown. Previous studies provide indirect evidence for gap junction coupling between subsets of neuropeptide-containing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Here we employ double labeling and retrograde tracing methods to investigate to what extent neuroendocrine and neuropeptide-containing neurons of the hypothalamus and brainstem express the neuronal gap junction protein connexin 36.</p> <p>Results</p> <p>Western blot analysis showed that connexin 36 is expressed in the PVN. In bacterial artificial chromosome transgenic mice, which specifically express the reporter gene Enhanced Green Fluorescent Protein (EGFP) under the control of the connexin 36 gene promoter, EGFP expression was detected in magnocellular (neuroendocrine) and in parvocellular neurons of the PVN. Although no EGFP/connexin36 expression was seen in neurons containing oxytocin or vasopressin, EGFP/connexin36 was found in subsets of PVN neurons containing corticotropin-releasing hormone (CRH), and in somatostatin neurons located along the third ventricle. Moreover, CRH neurons in brainstem areas, including the lateral parabrachial nucleus, also expressed EGFP/connexin 36.</p> <p>Conclusion</p> <p>Our data indicate that connexin 36 is expressed in subsets of neuroendocrine and CRH neurons in specific nuclei of the hypothalamus and brainstem.</p

Effect of Strain Magnitude on the Tissue Properties of Engineered Cardiovascular Constructs

Mechanical loading is a powerful regulator of tissue properties in engineered cardiovascular tissues. To ultimately regulate the biochemical processes, it is essential to quantify the effect of mechanical loading on the properties of engineered cardiovascular constructs. In this study the Flexercell FX-4000T (Flexcell Int. Corp., USA) straining system was modified to simultaneously apply various strain magnitudes to individual samples during one experiment. In addition, porous polyglycolic acid (PGA) scaffolds, coated with poly-4-hydroxybutyrate (P4HB), were partially embedded in a silicone layer to allow long-term uniaxial cyclic mechanical straining of cardiovascular engineered constructs. The constructs were subjected to two different strain magnitudes and showed differences in biochemical properties, mechanical properties and organization of the microstructure compared to the unstrained constructs. The results suggest that when the tissues are exposed to prolonged mechanical stimulation, the production of collagen with a higher fraction of crosslinks is induced. However, straining with a large strain magnitude resulted in a negative effect on the mechanical properties of the tissue. In addition, dynamic straining induced a different alignment of cells and collagen in the superficial layers compared to the deeper layers of the construct. The presented model system can be used to systematically optimize culture protocols for engineered cardiovascular tissues

Microtubule Dynamics Regulate Cyclic Stretch-Induced Cell Alignment in Human Airway Smooth Muscle Cells

Microtubules are structural components of the cytoskeleton that determine cell shape, polarity, and motility in cooperation with the actin filaments. In order to determine the role of microtubules in cell alignment, human airway smooth muscle cells were exposed to cyclic uniaxial stretch. Human airway smooth muscle cells, cultured on type I collagen-coated elastic silicone membranes, were stretched uniaxially (20% in strain, 30 cycles/min) for 2 h. The population of airway smooth muscle cells which were originally oriented randomly aligned near perpendicular to the stretch axis in a time-dependent manner. However, when the cells treated with microtubule disruptors, nocodazole and colchicine, were subjected to the same cyclic uniaxial stretch, the cells failed to align. Lack of alignment was also observed for airway smooth muscle cells treated with a microtubule stabilizer, paclitaxel. To understand the intracellular mechanisms involved, we developed a computational model in which microtubule polymerization and attachment to focal adhesions were regulated by the preexisting tensile stress, pre-stress, on actin stress fibers. We demonstrate that microtubules play a central role in cell re-orientation when cells experience cyclic uniaxial stretching. Our findings further suggest that cell alignment and cytoskeletal reorganization in response to cyclic stretch results from the ability of the microtubule-stress fiber assembly to maintain a homeostatic strain on the stress fiber at focal adhesions. The mechanism of stretch-induced alignment we uncovered is likely involved in various airway functions as well as in the pathophysiology of airway remodeling in asthma